PREPUBLICATION COPY, NOT TO BE REPRODUCED OR DISTRIBUTED WITHOUT PERMISSION OF THE AUTHORS

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1 PREPUBLICATION COPY, NOT TO BE REPRODUCED OR DISTRIBUTED WITHOUT PERMISSION OF THE AUTHORS Submitted to Regulatory Toxicology & Pharmacology Journal (February 21, 2012) Evaluation of Carcinogenic Hazard of Diesel Engine Exhaust Needs to Consider Revolutionary Changes in Diesel Technology Roger O. McClellan, a Thomas W. Hesterberg b and John C. Wall c a Advisor, Toxicology and Risk Analysis Quaking Aspen Place NE Albuquerque, NM 87111, USA b Director, Product Stewardship, Sustainability and Environmental Health Navistar, Inc Navistar Drive Lisle, IL 60552, USA c Vice President and Chief Technical Officer Cummins, Inc. 500 Jackson Street Columbus, IN a Corresponding Author: Telephone No Fax: Addresses: roger.o.mcclellan@att.net (R.O. McClellan) tom.hesterberg@navistar.com (T.W. Hesterberg) john.c.wall@cummins.com (J.C. Wall) 1

2 Table of Contents Abstract 1. Introduction 2. New Regulations Impacting on Diesel Exhaust Emissions 3. New Technology Diesel Developments Since the Mid-1980s 4. Periodic Health Assessments of Diesel Exhaust 5. IARC Evaluation of Carcinogenic Hazards 6. IARC 1988 Review of Diesel Exhaust, Gasoline Exhaust and Some Nitroarenes 7. Carcinogenic Hazard Evaluations of Specific Chemicals versus Complex Mixtures from Changing Technology 8. Advanced Collaborative Emission Study 9. Quantitative and Qualitative Differences in NTDE Compared to TDE - Traditional Diesel Exhaust Particulate Matter - NTDE Emissions are Lower than TDE - NTDE Particulate Matter has Different Composition than TDE - Semi-Volatile Organic Fraction of NTDE is Different than TDE - NTDE Contains Lower Amounts of Unregulated Pollutants than TDE - NTDE Particulate Mass is Fundamentally Different than TDE Particulate Mass - Lower Fine Particle Emissions from NTDE 10. Experimental Studies Evaluating Potential Health Effects of NTDE 11. Summary 12. Conclusions Acknowledgments Conflict of Interest Statement References

3 Abstract Diesel engines, a special type of internal combustion engine, use heat of compression, rather than electric spark, to ignite hydrocarbon fuels injected into the combustion chamber. Diesel engines have high thermal efficiency and, thus, high fuel efficiency. They are widely used in commerce prompting continuous improvement in diesel engines and fuels. Concern for health effects from exposure to diesel exhaust arose in the mid-1900s and stimulated development of emissions regulations and research to improve the technology and characterize potential health hazards. This included epidemiological, controlled human exposure, laboratory animal and mechanistic studies to evaluate potential hazards of whole diesel exhaust. The International Agency for Research on Cancer (1989) classified whole diesel exhaust probably carcinogenic to humans. This classification stimulated even more stringent regulations for particulate matter that required further technological developments. These included improved engine control, improved fuel injection system, enhanced exhaust cooling, use of ultra low sulfur fuel, wall-flow highefficiency exhaust particulate filters, exhaust catalysts, and crankcase ventilation filtration. The composition of New Technology Diesel Exhaust (NTDE) is qualitatively different and the constituents lower in concentrations than for Traditional Diesel Exhaust (TDE). We recommend that the 2012 IARC review of diesel exhaust should evaluate NTDE separately from TDE. Key words: cancer hazard; diesel exhaust; gasoline exhaust; engine technology; diesel particulate filter; three-way catalyst; ultra-low sulfur fuel; national ambient air quality standards; particulate matter; nitrogen dioxide 1

4 1. Introduction Diesel engines have found increasingly wide application in industry and in the transportation of goods and people around the world from the time of the invention of the technology by Rudolph Diesel in the 1890s to the present day. Rudolph Diesel, with an eye to the future, wrote on October 2, 1892 This machine is destined to completely revolutionize engine engineering and replace everything that exists (Mollenhauer and Tschoeke, 2010). His prophecy was only partially realized during the first century of diesel technology development. He could not have anticipated the recent revolutionary advances that have been made in diesel engine and fuel technology in response to more stringent emission regulations. Those advances in technology and the resulting major reductions in diesel engine exhaust emissions are the subject of this paper. Diesel engine exhaust is a complex mixture of carbon dioxide, oxygen, nitrogen, nitrogen compounds, carbon monoxide, water vapor, sulfur compounds and numerous low and high molecular weight hydrocarbons, and particulate matter. As will be related in this paper, the relative contribution of each of these compounds or classes of compounds have changed with advances in engine and fuel technology. A key concept well established in the internal combustion engine field is that emissions are influenced by both the engine (and exhaust after-treatment system) and the fuel being combusted. Pre-1980 diesel engines fueled with high sulfur content fuel produced exhaust that contained high concentrations of carbonaceous particulate matter with associated high concentrations of polycyclic aromatic hydrocarbons. The exhaust also contained high concentrations of Nitrogen Oxide (NO x ) and gas phase hydrocarbons. That exhaust was of concern because of its impact on visibility and for its potential health hazard. Concern for health impacts and, especially, cancer intensified when it was discovered that organic solvent extracts of the exhaust particulate matter were mutagenic in the Ames bacterial assays. The finding that extracts of diesel exhaust particulate matter contained mutagenic chemicals was viewed as presumptive evidence that exposure to diesel exhaust particulate matter could pose a carcinogenic hazard. This presumptive evidence had three related impacts. First, it stimulated a multi-faceted international research effort to clarify the potential health hazards of exposure to diesel exhaust. This included epidemiological studies, controlled human exposure studies, laboratory animal bioassays and mechanistic studies using both in vivo and in vitro approaches. The research findings were reported in the peer-reviewed literature and periodically 2

5 integrated and evaluated to characterize human health hazards of exposure to diesel exhaust. Most significantly, health hazard assessments focusing on carcinogenic hazard were conducted by international organizations such as the International Agency for Research on Cancer (IARC) and national organizations such as the National Toxicology Program (NTP) in the United States. Second, the presumptive evidence of possible human health hazard stimulated the issuance of increasingly stringent regulations to limit diesel exhaust emissions and, in turn, ambient air concentrations and human exposures. Third, the regulations stimulated research and development efforts that would lead to manufacture and marketing of new technology diesel engines that would meet those more stringent regulations. In this paper, we briefly recount the key regulatory issues of concern for diesel engines and fuels focusing on emission limits and the characterization of diesel exhaust with regard to its potential carcinogenicity. This paper focuses on regulations and standards promulgated in the United States. However, similar regulations were also promulgated in Europe and in other economically advanced countries around the world (Bauner et al. 2009). Thus, there has been regulatory pressure from around the globe to develop new technology diesel engines and fuels, which produce markedly lower exhaust emissions. Hesterberg et al. (2005) coined the term, New Technology Diesel Exhaust (NTDE) to describe the emissions from post-2006 diesel engines and from earlier model diesel engines retrofitted with exhaust after-treatment devices and using ultra-low sulfur fuels. In contrast, Traditional Diesel Exhaust (TDE) refers to emissions from pre-1988 diesel engines sold and in use prior to the U.S. EPA Heavy-Duty Diesel Emission Particulate Standards as well as the exhaust from transitional engines marketed from 1988 through 2006, a period of continuous improvements in diesel engine technology. This paper describes the quantitative and qualitative differences between TDE and NTDE. The diesel exhaust particulate matter that is a prominent constituent in TDE is shown in Figure 1. Soot aggregates like these are not present in NTDE. The emissions of particulate mass in NTDE is substantially lower (less than 1%) than those emitted from 1988 engines and does not contain elemental carbon particles like those in TDE. The specific chemical constituents found in TDE are also substantially reduced in concentration in NTDE. This reduction in concentration is so profound that we recommend that future carcinogenic hazard reviews on diesel engine exhaust and its constituents, such as those to be conducted in the near 3

6 future by IARC and the NTP, evaluate and classify the potential carcinogenic hazard of NTDE separately from that of TDE, either as whole diesel exhaust or as diesel exhaust particulates. 2. New Regulations Impacting on Diesel Exhaust Emissions In the United States, the stage was set for the development of improved, low emission diesel technology by passage of the Clean Air Act (CAA) Amendments of 1970 which substantially strengthened the regulatory authority available for dealing with ambient air quality (CAA, 1970). The U.S. Environmental Protection Agency (EPA) was created by Executive Order almost simultaneously with passage of the CAA and began operation on December 2, 1970 (Nixon, 1970). The EPA was delegated the authority to implement the CAA s numerous provisions. One section of the CAA, as amended, called for the establishment of National Ambient Air Quality Standards (NAAQS) for criteria pollutants. The criteria pollutants included Particulate Matter (PM), Hydrocarbons (HC), Nitrogen Dioxide (NO 2 ), Sulfur Dioxide (SO 2 ), and Carbon Monoxide (CO), all of which were prominent constituents in the exhaust of circa 1970 diesel engines. In addition, photochemical oxidants (with ozone later identified as the indicator) was listed as a criteria pollutant. Ozone is formed in the atmosphere in the presence of sunlight by chemical reactions among NO x and Volatile Organic Compounds (VOCs), which are emitted in diesel exhaust. Another section of the CAA provided for the regulation of Hazardous Air Pollutants (HAPs), agents whose emissions are typically related to specific sources, through the setting National Emission Standards for Hazardous Air Pollutants (NESHAPS). Very slow progress was made in the 1970s and 1980s in setting NESHAPs, in part, due to the challenge of establishing standards for agents that were identified as posing a potential carcinogenic hazard. This prompted a change with the CAA Amendments of 1990 to an approach based on first implementing emission limits based on Maximum Achievable Control Technology on an industry sector by sector basis, for example, the pulp and paper industry (CAA, 1990). This was to be followed by an assessment of any Residual Risk that needed to be addressed through additional regulations and emission controls. Other sections of the CAA specifically provide for setting standards for engine emissions including emission standards for diesel engines. These standards are based on concern for consideration of the potential health effects of the emissions. However, the specific standards 4

7 are not linked to achieving a specified, acceptable level of associated health risk, but rather have a strong technology-forcing character. In short, each progressively more stringent emission standard has been viewed as achievable with the advanced technology in hand or, in some cases, with an eye to new technology on the horizon or anticipated to be developed. Indeed, the progressively more rigorous diesel engine emission standards can be viewed as analogous to Maximum Achievable Control Technology standards. Using the legislative framework of the CAA, the EPA has issued a series of regulations (Table 1) that have impacted the development and deployment of new technology diesel equipment and the use of improved diesel fuel. The myriad of regulations promulgated since the earlier IARC (1989) Review can be summarized as follows: (i) diesel fuel sulfur levels for on-road vehicles have been reduced from 500 ppm and higher to less than 15 ppm; (ii) Heavy-Duty On Highway (HDOH) diesel engine PM emission standards have been reduced by 90%, from 0.10 g/bhp-hr to 0.01 g/bhp-hr (Fig. 2); (iii) HDOH diesel engine NOx emission standards have been reduced by more than 90%, from 4.0 g/bhp-hr to 0.20 g/bhp-hr (Fig. 3); (iv) non-road diesel engine PM emission standards have been reduced by more than 90%, from 0.60 g/bhp-hr to 0.01 (or 0.02) g/bhp-hr; and (v) non-road diesel engine NOx emission standards have been reduced by more than 90%, from approximately 5.6 g/bhp-hr (or higher) to 0.30 g/bhp-hr. The issuance of these increasingly stringent emission standards has been bolstered by changes over the last four decades in the National Ambient Air Quality Standards (NAAQS) for Particulate Matter (PM) (Table 2), Ozone (O 3 ) (Table 3) and Nitrogen Dioxide (NO 2 ). Each of the NAAQS consists of four elements; indicator, averaging time, concentration and statistical form; the latter two elements together determine the stringency of the standard. As may be noted in Table 2, the indicator for the initial PM NAAQS set in 1971 was Total Suspended Particulates (TSP) (essentially all particles that are sampled with a high-volume sampler which includes particles up to about 40 micrometers in aerodynamic diameter). In 1987, the indicator was changed to Particulate Matter, 10 micrometers aerodynamic diameter (PM 10 ). In 1997, a second 5

8 PM indicator was added, Particulate Matter, 2.5 micrometers aerodynamic diameter (PM 2.5 ). In 2006, the PM 10 NAAQS was revoked. The particles contained in TDE are less than 2.5 micrometers and, most substantially, smaller than 0.5 micrometers aerodynamic diameter (Kittelson, 1998). Thus, they are present in TSP, PM 10 and PM 2.5. However, as the indicator for the Particulate Matter NAAQS shifts from TSP to PM 10 to PM 2.5, a constant concentration of TDE particulate matter in the sampled air represents a larger portion of the sampled PM as the indicator shifts to smaller particles. As a result, each change in the indicator for the PM NAAQS has led to increased pressure on reducing diesel exhaust particulate emissions, since they represent a greater portion of the PM inventory that might potentially be controlled. For example, 1 µg of TDE/m 3 as a portion of the annual NAAQS set for TSP (1971) at 175 µg/m 3, for PM 10 (1987) at 50 µg/m 3 and for PM 2.5 (1997) at 15 µg/m 3 represented 1.3%, 2.0% and 6.7%, respectively, of the annual standard. The PM NAAQS set in 2006 is currently under review as part of the periodic updating of each NAAQS specified by the CAA. That review has focused on potential increased stringency with reductions in the annual PM 2.5 NAAQS now set at 15 µg/m 3 and, perhaps, the 24-hour PM 2.5 NAAQS now set at 35 µg/m 3. The review process has been delayed and is now scheduled to be completed in Any increase in the stringency of the PM 2.5 NAAQS will bring increased pressure on reducing all sources of PM 2.5 including diesel exhaust particulate emissions. In the case of the NAAQS for photochemical oxidants, the indicator and associated measurement methods set in 1971 for photochemical oxidants was changed in 1979 to Ozone. The averaging time shifted in 1997 from the highest 1-hour concentration to the highest 8-hour average concentration. The changes in the NAAQS for Ozone have not been as dramatic as for PM. However, the level and statistical form of the 8-hour averaging time standard needs to be considered within the context of natural background concentrations of ozone. Wang et al. (2009) used a global chemical transport model (GEOS-Chem) with a 1 times 1 horizontal resolution to quantify daily maximum 8-hour average concentrations in the U.S. surface air. They found that eliminating U.S. anthroprogenic emissions of Ozone precursors (NOx) and volatile organic compounds would maintain surface Ozone concentrations in the U.S. below 60 ppb at all times. Zhang et al. (2011) extended the modeling of Wang et al. (2009) using a horizontal resolution of 1/2 times 2/3. They found background ozone (4 th highest 8-hour average) concentrations exceeding 60 ppbv in the Intermountain Western U.S. and suggested this region would require 6

9 special consideration if the Ozone NAAQS were revised to the ppbv range as has been proposed. The NAAQS for Ozone is currently under review as part of the periodic 5-year review cycle specified by the CAA. McClellan (2011) has provided perspective on the Ozone NAAQS review which has focused on reductions from 75 ppb, the highest 8-hour average set in 2008, to 60 to 70 ppb with attainment based on the fourth highest daily maximum 8-hour concentration, averaged over 3 years. That review should be completed in 2013 or Needless to say, the increased stringency of the Ozone NAAQS, and the potential for an even more stringent standard will place more pressure on reducing NO x and VOC emissions from all sources, including diesel engines. The original NAAQS for NO 2 was set in 1971 with NO 2 as the indicator, an annual averaging time, a level of 53 ppb and a form based on the annual arithmetic average. The NO 2 NAAQS was re-evaluated in 1985 and 1996 and retained without revisions. In 2010, the NO 2 NAAQS was revised significantly. The primary annual NO 2 NAAQS was retained and a new 1- hour averaging time standard was introduced with the level set at 100 ppb. The form was set at the 3-year average of the 98 th percentile of the yearly distribution of 1-hour daily maximum NO 2 concentrations. The 1-hour standard places emphasis on reducing NO 2 emissions from on-road vehicles, including diesel-powered vehicles, in an effort to reduce ambient NO 2 levels near roadways. The CAA (1970, 1990) delegates to the individual states responsibility for air quality programs to monitor the criteria air pollutants and, most importantly, put in place programs to assure that the individual NAAQS are attained. The details of those programs are beyond the scope of this paper. Suffice it to note, the individual states that have areas whose air quality does not meet or attain the individual NAAQS must create State Implementation Plans (SIPs). The SIPs must outline a strategy for bringing non-attainment areas into attainment with each of the NAAQS. The activities developed and described in the SIPs extend to planning for changes in the deployment and use of technologies such as diesel engines that may impact on air quality. By way of background, regulatory efforts to reduce emissions from gasoline-fueled vehicles preceded the major regulatory initiatives for diesel-fueled engines. The EPA Clean Fuel program established standards in 1973 that gradually reduced the amount of lead in gasoline (Colucci, 2004). The lower Lead content reduced health risks in two ways. First, it directly reduced the exhaust emissions of lead, a known neurotoxicant. Second, elimination of lead in 7

10 gasoline was critical to enabling the use of advanced after-treatment technologies such as 3-way catalytic converters that reduce the emissions of CO, NO x and hydrocarbons in exhaust from gasoline-fueled vehicles. The presence of even trace levels of Lead in the fuel and, in turn, in the exhaust poisoned the catalyst in the exhaust treatment system rendering them ineffective. The CAA Amendments of 1990 and EPA regulations banned lead in gasoline after If those changes had not been made, air quality improvement would not have occurred and the literature on gasoline exhaust related health effects might have been quite different in 1988 and today. The reduced emissions from gasoline fueled vehicles and associated reductions in human health hazards were already being viewed in 1988 as a technological success story. However, additional improvements in gasoline engine technology, reduction of the sulfur content of gasoline, and reformulation of gasoline have resulted in further reductions in emissions from gasoline-fueled vehicles. Colucci (2004) and Twigg (2005) have provided a historical review of this extraordinary technology success story emphasizing the critical role of three-way catalytic converters to markedly reduce exhaust emissions of hydrocarbons, carbon monoxide and nitrogen oxides from gasoline-fueled engines. Indeed, in a manner analogous to our discussion of TDE and NTDE, it is appropriate to separately consider Traditional Gasoline Exhaust (TGE) and Modern Gasoline Emissions (MGE). This shift from TGE to MGE occurred rapidly starting in the 1970s with removal of lead from gasoline and progressive reductions in the sulfur content of gasoline allowing the introduction of 3-way catalysts in the exhaust system. The 1988 IARC review of gasoline engine exhaust was largely based on TGE. The June 2012 review of gasoline engine exhaust should consider the distinction between TGE and MGE. All of the regulations noted in Table 1, taken together, resulted in the need for and implementation of fundamental changes and advancements in the design, performance, sophistication and efficiency of diesel engine systems and the fuels upon which they operate in order to meet the regulations. This, in turn, has yielded profound changes in the concentrations and chemical composition of the exhaust from diesel engines since the last IARC carcinogen hazard classification review was conducted in 1988 (IARC, 1989). The net result is a technological success story similar to that achieved earlier for gasoline-fueled vehicles. 3. New Technology Diesel Developments Since the Mid-1980s The comprehensive regulatory programs enacted to reduce diesel emissions to near-zero levels have resulted in a major paradigm shift in diesel engine emission control technologies 8

11 since 1989 (Fig. 4). What started as evolutionary advances transitioned to revolutionary advances that markedly reduced and changed diesel engine emissions. Diesel emission control strategies have moved from the earlier engine-based designs and specific hardware improvements to fully integrated designs and systems -- systems that encompass improved diesel fuels with ultra-low sulfur content, improved diesel engine components, catalyzed exhaust aftertreatment systems, and electronic sensing and control systems (Colucci, 2004; Dollmeyer et al. 2007; Charlton et al. 2010; Bauner et al. 2008; Johnson, 2010, 2011; Tschoeke et al. 2010). The fully integrated systems approach of the new technology has resulted in more than an order-of-magnitude emission reductions and, in many cases, the virtual elimination of the emitted compounds that were of concern at the time of IARC s evaluation of traditional diesel exhaust in 1988 (Liu et al. 2008a, 2008b; 2009a, 2009b; 2010; Khalek et al. 2011). The myriad of technological advancements that have been developed over the past two decades through the integrated approach to reduce diesel emissions can be summarized as follows: (i) diesel engine control systems are now fully electronic and computerized, not mechanical, which allows for very precise, second-by-second management of the fuel injection and combustion processes; (ii) fuel-injection pressures and fuel atomization have increased dramatically through the introduction of high-pressure fuel-injection systems and turbochargers, which promote more complete and clean combustion; (iii) diesel exhaust cooling systems have advanced to control NOx emissions through sophisticated fuel-injection timing and rate-shaping, exhaust gas management, and enhanced charge-air cooling systems; (iv) diesel oxidation catalysts have advanced to the point where they can allow for the virtual elimination of hydrocarbons and other organic emission species under a broad range of operating conditions; (v) filters or coalescers have been installed in crankcase ventilation systems to reduce significantly the particulate matter emissions from crankcase 9

12 gases; and (vi) the introduction of ultra-low sulfur diesel ( ULSD ) fuels, defined in the USA as having less than 15 ppm Sulfur, has allowed for the deployment of wall-flow diesel particulate filters ( DPFs ), and the use of catalysts which have fundamentally changed the composition of diesel particulates while reducing their emissions to near-zero levels. Taken together, the foregoing new-technology diesel engine system components (specifically oxidation catalysts, fully integrated electronic control systems, and wall-flow DPFs capable of achieving the 0.01 g/bhp-hr PM standard) and the use of ULSD have resulted in newtechnology diesel engines. As we describe later, the resultant New Technology Diesel Exhaust (NTDE) is fundamentally different, both quantitatively and qualitatively, from the uncontrolled traditional diesel exhaust (TDE) that was the subject of the 1988 IARC evaluation process. 4. Periodic Health Assessments of Diesel Exhaust Another impetus for the development of diesel regulations and technology came from the periodic health assessments conducted by international and national organizations (Table 4). The most influential carcinogenic hazard assessments are those conducted by the International Agency for Research on Cancer (IARC). The IARC process will be described in detail in the next section. The IARC review held in 1988 and published in 1989 classified whole diesel exhaust in Group 2A, probably carcinogenic to humans, based on evidence from exposure evaluations, epidemiological investigations, laboratory animal studies and supporting information (IARC, 1989). The same IARC Working Group evaluated whole gasoline exhaust and classified it in Group 2B, possibly carcinogenic to humans. The basis for those overall evaluations will be discussed later. The carcinogenic hazard classification for diesel technology was also noted by the International Program on Chemical Safety (IPCS) in its Environmental Health Criteria Report (No. 171) for Diesel Fuels and Exhaust Emissions (IPCS, 1996). The California Air Resources Board (CARB) listed particulate emissions from diesel-fueled engines as a toxic air contaminant (TAC) based on its carcinogenicity (CARB, 1998a,b,c). The 9 th Report on Carcinogens (NTP, 2000), prepared by the National Toxicology Program (NTP), listed diesel exhaust particulates as reasonably anticipated to be a human carcinogen (NTP, 10

13 2000). The U.S. Environmental Protection Agency, in its Health Assessment Document for Diesel Engine Exhaust, classified diesel engine exhaust as likely to be carcinogenic to humans (EPA, 2002). It is important to note that the IARC overall evaluation and, later, that of the U.S. EPA, was for diesel engine exhaust while CARB and NTP classified particulate emissions from diesel-fueled engines and diesel exhaust particulates, respectively. The focus of CARB and the NTP was on particles present in TDE such as those shown in Figure 1, particles that have been virtually eliminated from NTDE. As will be reviewed later, TDE is a complex mixture of gases, semi-volatile chemicals and particulate matter adsorbed and with absorbed chemicals. In contrast, NTDE consists largely of gases with extraordinarily low concentrations of particulate matter. All of these hazard assessment reports noted that diesel engine technology was changing and that when advances were made it would be appropriate to review the general applicability of the health hazard conclusions based on traditional technology to the newly emerging technology developed. IARC expressly noted that changes are expected in the future (IARC, 1989). The EPA Health Assessment Document (EPA, 2002) specifically stated The health hazard conclusions are based on exhaust emissions from diesel engines built prior to the mid-1990s. As new and cleaner diesel engines, together with different diesel fuels, replace a substantial number of existing engines, the general applicability of the health hazard conclusions will need to be re-evaluated. The IARC has announced it will review the classification of diesel and gasoline engine exhausts and some nitroarenes at a meeting to be held June 5-12, 2012 in Lyon, France (IARC, 2012a). This will be the first carcinogenic hazard assessment for diesel exhaust conducted since substantial advances have been made in technology that have profoundly reduced diesel exhaust emissions and fundamentally changed their composition. It can be anticipated that other authoritative bodies such as the WHO, U.S. EPA, CARB and NTP will also review their previous hazard classification actions on diesel engine exhaust. Indeed, the NTP has already announced its intention to review the classification of diesel exhaust particulates for inclusion in the 13 th Report on Carcinogens (NTP, 2012). To a variable degree, those organizations are likely to take account of the actions of IARC at its June 2012 meeting while still fulfilling their own independent mandates. 11

14 5. IARC Evaluation of Carcinogenic Hazards Cancer, a family of diseases characterized by new and uncontrolled growth of tissue, has long been of concern to humans because of its frequent occurrence, particularly late in life. It is estimated that in industrialized societies, 40% of individuals will develop cancer sometime during their life and about one in four individuals will die with cancer (Ayres et al. 2010). Lung cancer is one of the most common cancers with a large portion of cases attributed to cigarette smoking. The role of multiple agents in causing cancer has received substantial attention stimulated by the view that if the causes of cancer could be identified, then exposure to the substances could be reduced or, perhaps, even eliminated. Not surprisingly, IARC after its establishment in 1965 received frequent requests for information on known or suspected carcinogens (IARC, 2006). In response, the IARC in 1969 initiated a program on the evaluation of the carcinogenic risk of chemicals to humans, a program that involves the production of critically evaluated monographs on a wide range of agents. The scope of the IARC monographs soon broadened to include groups of related chemicals, complex mixtures, occupational exposures, physical and biological agents and lifestyle factors. This broad scope was recognized in 1988 with the title of the document series changed to IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. The Preamble to each IARC Monograph includes a statement of the scientific principles used to evaluate and classify various agents as to their potential for causing cancer in humans (IARC, 2006). As the Preamble notes A Cancer hazard is an agent that is capable of causing cancer under some circumstances, while a cancer risk is an estimate of the carcinogenic effects expected from exposure to a cancer hazard. The Monographs are an exercise in evaluating cancer hazards despite the historical presence of the word risks in the title (IARC, 2009). As an aside, evaluation of health risks requires knowledge of the intensity and duration of exposure to an agent and the potency of the hazardous agent for causing the health effect of concern, for example, cancer. The Preamble makes note of the historical use of strength of evidence in evaluating carcinogenicity and then proceeds to state it should be understood that Monograph evaluations consider studies that support a finding of a cancer hazard as well as studies that do not. The IARC convenes a separate Working Group of experts to develop each Volume of the Monographs. The Working Group members generally have published significant research 12

15 related to the carcinogenicity of the agents being reviewed. The Monograph evaluation and classification process only uses papers that have been published and accepted for publication in the openly available scientific literature. Each Monograph consists of six sections: (a) exposure data, (b) studies of cancer in humans, (c) studies of cancer in experimental animals, (d) mechanistic and other relevant data, (e) summary, and (f) evaluation and rationale. The Exposure Data section contains general information on each agent. This includes the composition of the agent, analysis and detection methods, production and use, and occurrence and exposure. It is noteworthy that the Preamble explicitly notes Whenever appropriate, other information, such as historical perspectives --- may be included. This will be especially important for the upcoming evaluation of diesel exhaust in view of the marked changes in diesel engine exhaust that have occurred with recent technological advances which changes are the focus of this review. Studies of humans always have a central role in the IARC evaluation and classification process. This includes multiple types of epidemiological studies cohort studies, case-control studies, correlation (or ecological) studies and intervention studies. Since the 1988 IARC review, numerous additional epidemiological studies have been conducted and published on TDE and will be central to the 2012 re-evaluation of diesel exhaust. Ward et al. (2010) noted the role of epidemiological evidence in potentially upgrading the IARC classification of diesel exhaust and some 19 other agents. Hesterberg et al. (2006, 2012b) and Gamble (2010) have reviewed and commented on the strengths and weaknesses of the studies. The Health Effects Institute (HEI, 2002) has also reviewed the epidemiological studies. The HEI report made specific note of the absence of a well-accepted marker of exposure to diesel exhaust, what we now call TDE. Since new diesel technology and improved fuels have only recently been introduced, epidemiological studies focusing on NTDE have not been conducted. Indeed, the very low concentrations of potentially hazardous chemicals in NTDE relative to the concentrations of these or similar chemicals from other sources in the workplace and ambient environment suggest that it may not be feasible to conduct epidemiological studies of NTDE even when the new technology has largely displaced the old traditional diesel technology, due to a lack of unique markers of low level NTDE exposures. 13

16 Studies of cancer in experimental animals have also traditionally had a key role in evaluating and classifying agents as to their human carcinogenic potential. In fact, the Preamble (IARC, 2009) notes All known human carcinogens that have been studied adequately for carcinogenicity in experimental animals have produced positive results in one or more animal species (Tomatis et al. 1989; Wilbourn et al. 1986). A number of well-conducted studies in experimental animals have evaluated the carcinogenicity of TDE and were reviewed in the earlier Monograph (IARC, 1989). A few additional chronic inhalation exposure studies with TDE have been conducted and published in the intervening years (Hesterberg et al. 2005; Mauderly and Garshick, 2009; Hesterberg et al. 2012b). As will be discussed later, a large scale chronic inhalation bioassay of NTDE is being conducted under the aegis of the Health Effects Institute (HEI) with joint funding from government and industry. In IARC Monographs prepared in recent decades, the section on Mechanistic and other relevant data have been an increasingly important part of each Monograph (IARC, 1991, 2005, 2006; Vainio et al. 1992, 1995). This includes information on toxicokinetics and mechanisms of carcinogenesis including physiological changes, changes in cell function and molecular changes such as genetic alterations. The Summary Section of each Monograph draws together in a concise manner the information on (a) exposure data, (b) cancer in humans, (c) cancer in experimental animals, and (d) mechanistic and other relevant data. The final element of each Monograph on an agent is the Evaluation and Rationale Section. This section evaluates the strength of the evidence for carcinogenicity arising from human and experimental data using standard terms. In addition, the strength of the mechanistic evidence is also characterized. The key descriptive phases for each kind of evidence are: sufficient evidence of carcinogenicity, limited evidence of carcinogenicity, inadequate evidence of carcinogenicity, and evidence suggesting lack of carcinogenicity. The basis for selecting from among those four descriptors is given in the Preamble (IARC, 2009). At the final step in the evaluation and classification process an overall evaluation is made of the carcinogenicity of the agent to humans. The IARC Carcinogenic Hazard Classification scheme is summarized in Table 5. The reviews and classifications are published in Monographs that are widely used around the world as the most authoritative sources of information on the cancer causing potential of 14

17 various agents and exposure circumstances. IARC recently published Monograph Volume 100 consisting of 6 parts (IARC, 2011a,b,c,d; 2012 a,b). These Monographs are summarized in six papers published in Lancet; pharmaceuticals (Grosse et al. 2009); biological agents (Bouvard et al. 2009); arsenic metals, fibres and dusts (Straif et al. 2009); radiation (El Ghissassi et al. 2009); chemical agents and related occupations (Baan et al. 2009) and tobacco, areca nut, alcohol, coal smoke and salted fish (Secretan et al. 2009). As of January 1, 2012, IARC has reviewed 942 substances and exposure circumstances with 107 classified in Group 1 (carcinogenic to humans), 59 in Group 2A (probably carcinogenic to humans), 267 in Group 2B (possibly carcinogenic to humans), 508 in Group 3 (not classifiable) and 1 in Group 4 (probably not carcinogenic to humans) (IARC, 2012b). 6. IARC (1989) Review of Diesel Exhaust, Gasoline Exhaust and Some Nitroarenes In convening a Working Group of Experts, IARC frequently takes advantage of their expertise to review several related agents or substances at the same time. That was done in the June 14-21, 1988 meeting when diesel and gasoline engine exhaust and some nitroarenes were evaluated (IARC, 1989). It was natural to review the information on exhaust from diesel and gasoline-fueled engines at the same time, since those are the dominant liquid hydrocarbon fuels used around the world. Some nitroarenes were included in the 1988 review because during the mid-1980s considerable attention was being given to this class of compounds as mutagenic and putative carcinogenic agents within engine exhaust emissions. By way of background, it is useful to recount some of the deliberations that took place at the beginning of the 1988 review. One of us (Roger O. McClellan) participated in that review as Chair of the animal studies subgroup. Two viewpoints were advanced by different participants as the Working Group began the review session in Lyon, France. Some participants expressed the view that it might be appropriate to consider as a broad class internal combustion engine exhaust combining the evidence for both diesel engines and gasoline engines. Those advancing this approach noted that many chemical compounds found in engine exhaust were common to both types of engine exhaust and that some epidemiological evidence was based on populations for which the exposures could not be specified as being primarily from diesel or gasoline engines; the exposures were mixed. Points favoring the separate evaluation of diesel and gasoline engine exhaust were the existence of clear quantitative and qualitative differences in the exhaust from the two types of engines. It was also noted that the carbonaceous component and 15

18 associated chemicals emitted by diesel engines were of particular concern (Recall Fig. 1). Moreover, it was apparent from a cursory review of the long-term animal studies with diluted whole engine exhaust that the results from studies with the diesel exhaust were different from those with gasoline engine exhaust exposure. Those who favored lumping the two types of engines countered by noting that both extracts of diesel exhaust particles and condensates/extracts of gasoline engine exhaust yielded positive results in in vitro studies. It is noteworthy that some of the gasoline engine condensate/extract studies were conducted with TGE and some with NTGE. Samples of gasoline engine exhaust studied at the U.S. EPA as part of their Comparative Potency project (Albert et al. 1982; Lewtas, et al. 1983) were from a maltuned gasoline-fueled vehicle. It was necessary to mal-tune the engine in order to obtain sufficiently large samples of particulate material to use in the biological studies. In the end, the decision was made in 1988 to provide separate evaluations of the different kinds of evidence, when available, for whole diesel engine exhaust, gas-phase diesel engine exhaust, extracts of diesel engine exhaust particles, whole gasoline engine exhaust, condensates/extracts of gasoline engine exhaust and engine exhaust (unspecified as from diesel or gasoline engines) and provide overall evaluations for diesel engine exhaust and gasoline engine exhaust as shown in the two left hand columns of Table 6. We will discuss the four columns on the right side of Table 6 later. As is customary in IARC evaluations, the Working Group considered the information available on the composition of engine exhaust and exposure data as background for evaluating the health effects information. We will discuss key conclusions drawn in that section of the Monograph (IARC, 1989) later when we compare and contrast TDE and NTDE. The core of every IARC evaluation is the carcinogenicity data available from human studies and laboratory animal studies. The first step in the evaluation process is to consider the quality of the various studies. In a second step, the studies characterized as well-designed and well-conducted are evaluated for the strength of the evidence for an association between exposure and carcinogenic outcome. The human data evaluation in 1988 focused on five cohort studies and five case-control studies that evaluated the risk of lung cancer and exposure to diesel exhaust, and three cohort studies and four case-control studies that evaluated the risk of bladder cancer and exposure to diesel exhaust. In all cases, the exposure involving TDE had begun as early as the 1940s. 16

19 Inadequacies in the exposure characterization were a major limitation to varying degrees in all of the epidemiological studies. There also were significant difficulties in identifying gradients in exposure-response relationships. The Working Group s summary evaluation of the epidemiological evidence was that there is limited evidence for the carcinogenicity in humans of diesel engine exhaust. The same Group concluded that there is inadequate evidence for the carcinogenicity in humans of gasoline engine exhaust. The 1988 review of experimental animal data focused on five well-conducted studies in which two different strains of rats were exposed chronically to low dilutions (high exhaust concentrations) of whole diesel exhaust. Four of the studies involved exhaust from light-duty engines and one involved exhaust from a heavy-duty engine. Three of the studies with light-duty diesel engine exhaust and the study with heavy-duty diesel engine exhaust showed a tumorigenic effect in the rats. Based on the terminology described earlier in this paper, those studies would now be considered as having been conducted with TDE. In contrast, the studies conducted with other species (mice and Syrian Hamsters), frequently conducted in parallel with the rat studies did not show a tumorigenic effect. Two of the Laboratories, the Fraunhofer Institute in Hanover, Germany and the Battelle Memorial Institute in Geneva, Switzerland, conducted parallel studies with animals exposed to low dilutions (high concentrations) of whole gasoline engine exhaust. Published results from only one of these studies were available at the time of the IARC review. It is noteworthy that information is now available from chronic inhalation studies with rats exposed to whole-gasoline engine exhaust from engines without catalytic treatment of exhaust (TGE) and from engines with catalytic treatment of exhaust (NTGE) (Brightwell et al. 1989; Heinrich et al. 1986). The gasoline engine exhaust either without or with catalytic treatment did not produce a tumorigenic response. It is useful to consider the complete evaluation offered by the Working Group (Table 6) (IARC, 1989). The finding of inadequate evidence for carcinogenicity in experimental animals of gas phase diesel engine exhaust (particles removed) is especially noteworthy since, as will be described later, NTDE is essentially free of particles. Indeed, the exhaust after-treatment systems with catalyst and particulate traps results in NTDE that is quite similar in composition and concentration to the exhaust from 3-way catalyst equipped gasoline engines (NTGE) as we 17

20 will discuss later. Recall that the IARC Panel concluded There is inadequate evidence for the carcinogenicity in experimental animals of whole gasoline engine exhaust. The overall evaluations of the Working Group were Diesel engine exhaust is probably carcinogenic to humans (Group 2A) and Gasoline engine exhaust is possibly carcinogenic to humans (Group 2B). Based on the definitions provided earlier in this paper, we view the diesel exhaust as TDE and the gasoline exhaust as TGE. It is apparent that the overall evaluation for diesel engine exhaust was heavily influenced by the epidemiological findings (limited evidence) and the findings in the experimental studies with rats (sufficient evidence). The Monograph made note of the changes in the lungs of rats exposed to the highest concentrations of diesel exhaust including altered clearance when exposures were above about 300 mg-hours per week. It was not until after the 1988 Review that it was recognized that prolonged exposure of rats to high concentrations of several kinds of poorly soluble particles (not just diesel soot particles) impaired clearance mechanisms, produced lung burdens of particles in excess of that projected from lower level exposures, produced chronic pathology and, most significantly, resulted in an excess of lung tumors (McClellan, 1996; Wolff et al. 1987, 1989). Indeed, the EPA Health Assessment Document (2002) using the new information concluded Overload conditions are not expected to occur in humans as a result of environmental and most occupational exposures to DE. Thus, the rat lung tumor response ( under overload conditions phrase added) is not considered relevant to an evaluation of the potential for human environmental exposure-related hazard. This mechanistic information on TDE has been critically reviewed and evaluated (Hesterberg et al. 2005, 2011, 2012b). With this as background, it can be anticipated that the June 2012 IARC evaluation of diesel exhaust will focus on three areas. First, it is anticipated that the Working Group will critically review both the old and new epidemiological findings for TDE. Second, it will be important for the Working Group to critically review the large body of mechanistic evidence that now exists on how long duration, high concentration exposures of rats to poorly soluble particles, such as the elemental carbon core particles found in TDE, produce lung tumors and the relevance of those findings to evaluating human hazards (Greim et al. 2001; HEI, 1995, 1999; Hesterberg et al. 2005, 2012b; ILSI, 2000; McClellan, 1996; USEPA, 2002; Watson and Valberg, 1996). In the foregoing statement, we have purposefully identified TDE as the agent being re-evaluated. This has been done recognizing that all of the epidemiological studies have been conducted on 18

21 populations of workers exposed to diesel exhaust from engines with limited emission controls (TDE). As will be described below, the exhaust emissions of the NTDE are substantially lower in concentration and different in composition from the TDE. Third, based on the substantial quantitative and qualitative differences between TDE and NTDE as reviewed in this paper, we recommend that the Working Group develop a separate cancer hazard classification for NTDE. 7. Carcinogenic Hazard Evaluations of Specific Chemicals versus Complex Mixtures from Changing Technology The vast majority of IARC evaluations (IARC, 2012), excluding biological agents, can be placed in two categories; specific chemicals, or exposures to emissions of a specific technology. The two kinds of evaluations have some significant differences. A chemical, such as benzene or formaldehyde, is the same chemical today as it was a decade or a century ago. The uses of the chemical may change over time but its basic chemical properties do not change. However, knowledge of the carcinogenic hazard may change over time as a result of additional research and advances in scientific knowledge. Knowledge of human exposure may also change as a result of new measurements and changes in work place practices including control of exposure to the specific agent. Indeed, work place practices were likely influenced by the previous IARC classification of the carcinogenic hazard of the specific chemical. The situation for a complex agent such as diesel engine exhaust, gasoline engine exhaust, or man-made products such as glass wool fibers is different than that of a specific chemical. The physical properties of these complex agents may change over time with technological advances, including advancements made to reduce the hazardous properties of the agent. As discussed later, the concentrations of particulate matter in TDE have been steadily reduced over the last half century as diesel engine technology and fuels improved. Moreover, those evolutionary reductions and changes in TDE are simply not the same as the revolutionary reductions and changes in TDE pale by comparison with the reduced concentrations and changes in the composition of NTDE compared to TDE. For purposes of carcinogenic hazard evaluation, it is clear that TDE and NTDE are not equivalent; they need to be separately evaluated. The importance of separate evaluations and classifications for TDE and NTDE extends to the impact of the carcinogenic hazards evaluations on future use of diesel technology. The detailed evaluation and potential re-classification of TDE is beyond the scope of this review. However, it can be noted that the previous classification, Group 2A (probable human 19

22 carcinogen), for diesel exhaust could be reaffirmed or changed based on the current scientific evidence. Irrespective of the specific carcinogenic hazard classification, a classification in Group 1, 2A or 2B will serve as a continuing stimulus to limit TDE particulate emissions and reduce ambient concentrations of PM. If NTDE were to be considered as equivalent to TDE, a decision that we think would be inappropriate, such an approach could undermine the incentive for shifting from TDE to NTDE, all to the detriment of many decades of effort to improve diesel engine technologies, fuels, air quality, all with a goal of improving public health. The IARC has previously faced a similar situation in evaluating the carcinogenic hazard of agents impacted by technological change. An example was the most recent IARC review of man-made vitreous fibers (IARC, 2002). This was a re-evaluation of man-made mineral fibers that had occurred earlier (IARC, 1988). Between the initial review and the second review, the man-made vitreous fiber industry had conducted extensive research to better understand the determinants of fiber induced respiratory tract tumors in rats as a basis for understanding the potential human carcinogenic hazards of various man-made fibers (Hesterberg et al. 2012a). The Hesterberg et al. (2012a) paper reviews the highly successful effort linking product stewardship and science as a basis for the safe manufacture and use of fiber glass. The industry-sponsored research program demonstrated that the key determinant of fiber carcinogenicity in rats was the biopersistence of inhalable fibers in the respiratory tract. Protracted inhalation exposure of rats to high concentrations of poorly soluble and, hence, biopersistent fibers produced an excess of respiratory tract tumors. In contrast, exposures with similar concentrations and duration to more soluble, and hence, less biopersistent glass fibers did not produce an excess of respiratory tract tumors. Building on those critical scientific findings, the glass fiber manufacturers made major changes in the production process for glass wool fibers shifting to production of biosoluble glass fibers, except for certain highly specialized product lines which required very durable fibers. The IARC (2002) monograph acknowledged the changes and concluded that insulation glass wool continuous glass filaments, rock (stone) wool, and slag were not classifiable as to their carcinogenicity to humans (Group 3). The traditional special purpose fibers and Refractory Ceramic Fibers that were biopersistent in the respiratory tract when inhaled were retained in Group 2B. The European Commission (Bernstein, 2007; EU, 1997) adopted a formal directive for not classifying certain fibers as carcinogens based on their lack of biopersistence. More recently, 20

23 the 12 th Report on Carcinogens prepared by the U.S. National Toxicology Program concluded that Certain Glass Wool Fibers (Inhalable) were Reasonably Anticipated to be human carcinogens (NTP, 2011b, 2011c). Certain was defined in the supporting documentation as only certain fibers within this class specifically fibers that are biopersistent in the lungs or tracheobronchial region are reasonably anticipated to be human carcinogens. The California Office of Environmental Health Hazard Assessment (OEHHA, 2011) soon followed suit on November 18, 2011 by modifying its 1980 listing of Glass Wool Fibers (Airborne Particles of Respirable Size) as known to the state to cause cancer to a revised listing of Glass Wool Fibers (Inhalable and Biopersistent) as known to the State to cause cancer. The recognition by IARC, the EU, the US NTP, and California OEHHA that technological advances have resulted in safer products should create an incentive for phasing out of old products and a transition to safer new products. As we will discuss in the next section, it is our opinion that the current evidence strongly supports classifying NTDE separately from TDE and placing NTDE in Group 3, not classifiable as to its carcinogenicity to humans. The actions of IARC on this matter will have broad implications relative to the increasing attention being given to world-wide development and deployment of green products or technologies. Here we use the term green products or technologies as an umbrella term for new products or technologies that are intended to have reduced impact on the environment and human health as compared to the technology being replaced or reduced in use. In the case of diesel engines used in a myriad of on-road and other applications, there will be a long transition period as TDE units are replaced with NTDE units and ultra-low sulfur diesel fuel replaces high sulfur diesel fuel around the world. Regulations established by International and National government organizations will have a major role in determining the pace with which NTDE units are introduced and TDE units replaced. The regulatory activities of those organizations will be strongly influenced by the outcome of the IARC review June The already announced review by NTP of diesel exhaust particulates will likely be the first review conducted after the IARC review (NTP, 2012) and the outcome of that review will certainly have major impact in the USA. 8. Advanced Collaborative Emissions Study As new diesel technology began to be developed by individual companies, it became apparent that broad acceptance of the new technology would be enhanced by a complementary 21

24 collaborative effort that focused on characterization of engine emissions and potential health impacts. Ultimately, with strong support from industry what has become known as the Advanced Collaborative Emissions Study (ACES), program emerged. ACES is a cooperative, multi-party effort managed in a coordinated manner by two well-respected non-profit sciencebased organizations, the Health Effects Institute (HEI) and the Coordinating Research Council (CRC). The overall effort has been guided by an ACES Steering Committee, which is advisory to HEI and CRC. It includes representatives of the U.S. EPA, U.S. Department of Energy (DOE), California Air Resources Board, American Petroleum Institute, National Resources Defense Council, National Institutes of Occupational Safety and Health, engine manufacturers, emission control manufacturers, the petroleum industry and others. The HEI is a non-profit entity chartered in 1980 as an independent research organization to provide high-quality, impartial, and relevant science on the health effects of air pollution (HEI, 2012). Indeed, the creation of HEI traces to uncertainties in the late 1970s over the potential health effects of vehicle emissions, including diesel engine emissions. The HEI typically receives half of its core funds from the U.S. Environmental Protection Agency and half from the world-wide motor vehicle industry. Other public and private organizations periodically support special HEI activities such as the ACES Program. HEI does not have its own research facilities, but provides financial support to scientists in universities and research organizations to conduct research oriented to achieving HEI s research objectives. The CRC is a non-profit organization that directs and manages studies on the interaction between automotive/other mobility equipment and petroleum products (CRC, 2012). It traces its origins to a Committee of the Society of Automotive Engineers and became an independent organization in It does not have any research facilities; instead it sponsors research at universities and other research organizations to achieve its scientific objectives. Both the HEI and CRC have achieved world-wide recognition for sponsoring research on important air quality issues and for the rigorous review and subsequent publication of that research in the peer reviewed, open scientific literature. The organization, management and funding of ACES are described in the Preface to one of the initial HEI reports on the program (Mauderly and McDonald, 2012). That document summarizes the three phases of the ACES program as follows: 22

25 Phase 1: Extensive emissions characterization of four production-ready heavy-duty diesel (HHDD, i.e. gross vehicle weight larger than 33,000 lbs) engines and control systems designed to meet the 2007 standards for reduced PM. This phase was conducted at Southwest Research Institute (SwRI) in 2007 and 2008 and was the basis for selecting one HHDD engine/after-treatment system for health testing in Phase 3. Phase 2: Extensive emissions characterization of a group of production-intent engine and control systems meeting the 2010 standards (including more advanced NO controls to meet the more stringent 2010 NO x standards). This phase is to be conducted at SwRI during 2011 and Phase 3: Health effects assessment in rodents using one selected 2007 compliant engine system. This phase started in 2008 with the installation of a specially-designed emissions generation and animal exposure facility at the Lovelace Respiratory Research Institute (LRRI) and is being conducted in two Phases. Phase 3A included setting up the engine, characterizing the engine performance and emissions to make sure it was operating as intended, and generating and characterizing the exposure atmospheres in the animal inhalation chambers at three dilution levels. Phase 3B includes a 90-day inhalation study in mice and a chronic inhalation study in rats with health measurements at several time periods. In this paper, we repeatedly refer to results from the ACES Phase I engine emissions characterization effort. Thus, it is appropriate to briefly describe that activity. A research team, under the leadership of Imad Khalek at the Southwest Research Institute (SwRI) was selected to carry out the Phase 1 engine emission characterization activities. A description of the characterization effort is found in Khalek et al. (2011) with additional details in Khalek et al. (2010), the report issued by the CRC on the ACES Phase 1 effort. Four different engine manufacturers provided 2007 model year production engines for the characterization studies conducted at SwRI. All four engines were from product lines developed to meet the USEPA s stringent 2007 emissions standards; particulate matter, 0.01 g/bhp-hr; and nitrogen-oxides, 1.20 g/bhp-hr. The nitrogen oxides emissions standard was reduced to 0.20 g/bhp-hr for The specific engines tested were a Caterpillar C13 (430 hp), a Cummins ISX (455 hp), a Detroit Diesel Corporation Series 60 (455 hp) and a Mack MP7 (395 hp) manufactured by Volvo. It was anticipated that at the end of the Phase 1 characterization 23

26 effort at SwRI one of the engines would be identified to produce the exhaust emissions used in the Phase 3 health studies. Further, it was decided that it would be desirable to conduct characterization studies on the emissions from a companion engine so that two nearly identical engines would be available for the health studies. From the outset, it was agreed that the Phase 3B health studies would involve exposures to diluted exhaust of 16 hr/day, 5 days/week for up to 30 months, thus the ACES Phase 3B rat study will be longer than the two-year duration of typical NTP studies (NTP, 2011a). Further, it was understood that it would be important to have the engine operating under a rigorous variable load duty cycle. This led to a decision to create a 16-hour engine test schedule that would also be used in the characterization studies at SwRI. This allowed for a direct link between the Phase 1 characterization effort and the use of the engines and the same test schedule at the facility that would conduct the health studies. The details of that test cycle and its development are described in Clark et al. (2007). The cycle includes four 4-hour segments consisting of Federal Test Procedure (FTP) segments mixed with segments of the CARB 5-Modes driving cycles. It was designed to be representative of modern truck usage and included a broad range of engine loads and speeds reflecting both urban and rural (highway) driving. The 16-hr cycle also added useful information on emissions during particle filter regeneration, which does not occur during the shorter test cycles. Regeneration typically occurs once or twice during each integrated cycle. The Phase 1 engine exhaust characterization research was conducted with engines using ultra-low sulfur fuel meeting fuel standards for 2007 and beyond. Specifically, it contained 4.5 ppm sulfur, 26.7 vol% aromatics, carbon content of wt%, hydrogen content of wt%, oxygen by difference of 0.76 wt%, density of g/h, API gravity at 60 F of 33.8 density at 15 C of 855.6g/l and a Cetane Number of The HEI selected the Lovelace Respiratory Research Institute (LRRI) to conduct the core investigations of the potential health effects of NTDE. The LRRI research team has been actively involved in studying diesel engine emissions and other air quality issues since the late 1970s (McClellan et al. 1982, 1986). The Institute s research included conduct of one of the earliest chronic inhalation bioassays in rats (Mauderly et al. 1989) and another in mice (Mauderly et al. 1996a) exposed concurrently to diluted whole exhaust produced by a 5.7 L light-duty diesel engine manufactured by General Motors and operating on a fixed bed 24

27 dynamometer utilizing a variable load cycle. We view the diesel exhaust studied by Mauderly and colleagues as TDE. The development of modified engine/exposure facilities to accommodate a heavy-duty engine and the core ACES study at LRRI was initiated under the leadership of J.L. Mauderly and, after his retirement, continued under the leadership of J. McDonald. The core studies are chronic inhalation exposure bioassays in rats and mice exposed to three dilutions of whole diesel exhaust from an engine operating on a dynamic load cycle and fueled by ULSD fuel to simulate real world conditions. The study has the objective of testing the ACES program core (null) hypothesis Emissions from combined new heavy-duty diesel engines, after-treatment, lubrication and fuel technologies designed to meet the 2007 NO x and PM emission standards will have very low pollutant levels and will not cause an increase in tumor formation or substantial toxic health effects in rats and mice at the highest concentration of exhaust that can be used (based on temperature and NO 2 or CO levels) compared to animals exposed to clean air, although some biological effects may occur. The ACES Phase 3A effort carried out at Lovelace included preparation of the facilities for operation of one of the heavy-duty on-road diesel engines compliant with the 2007 USEPA emission standards. In addition, the diluted emissions delivered to the animal exposure chambers were characterized without animals in the chambers to provide a linkage to the extensive engine emissions characterization done at SWRI. The emissions characterization carried out at LRRI provided a basis for determining the plausible upper bound of exposure concentrations for critical constituents for the animal exposures and, thus, the desired dilution of whole exhaust. The HEI Oversight Committee had determined that the NO 2 concentration needed to be limited to a Maximum Tolerated Dose (MTD) of NO 2 based on an earlier HEIsponsored chronic inhalation exposure study of NO 2 alone reported by Mauderly et al. (1989, 1990). The MTD is the highest daily dose (or more correctly, exposure concentration) that does not cause overt toxicity (McConnell, 1996). The use of an MTD in a chronic study such as ACES provides a maximum likelihood of an excess of detecting late-occurring effects, such as cancer, in the animals exposed to the test agent compared to the occurrence in sham-exposed control animals. The earlier study by Mauderly et al. (1989, 1990) involved exposure of male F344/Crl rats to 9.5 ppm NO 2 for 7 hr/day, 5 days/week for up to 2 years. This equates to 66.5 ppm-hr/day 25

28 of exposure. They made extensive measurements of multiple indicators of biological changes after 12, 18 and 24 months of exposure. Key histopathological findings were mild hyperplasia of epithelium in terminal bronchioles and an extension of bronchiolar epithelial cell types into proximal alveoli, giving the appearance of respiratory bronchioles. Terminal bronchiolar walls were slightly thickened and eosinophilic. A slight inflammatory infiltrate of mixed cell type was occasionally found in alveoli adjacent to thickened bronchioles. The lesions progressed little with time, with the exception of a slight progression of the epithelialization of proximal bronchioles. The inflammatory response remained minimal. (Mauderly et al. 1990). Mauderly (2010) provides an overview of the ACES program, including the inhalation exposure studies in laboratory animal studies. A detailed HEI report of the ACES Phase 3A will soon be available (Mauderly and McDonald, 2012). The ACES Phase 3B animal health studies have already been initiated at LRRI. Those studies were briefly described by Mauderly (2010) and are described in detail in a soon to be released HEI report (McDonald et al. 2012). The animal studies involve exposure (16 hours/day, 5 days/week) to graded concentrations from engines from the SwRI characterization work. The engine at LRRI is fueled with USEPA 2007 compliant ultra-low sulfur fuel (< 15 ppm sulfur). The commercial diesel fuel used in the initial Phase 3A and 3B research contained 3-5 ppm sulfur, volume % aromatics and a cetane index of Three exposure levels with targeted NO 2 concentrations of 4.2, 0.8 and 0.1 ppm, and clean air control are being studied. The resulting dilution ratios of clean air to raw exhaust are approximately 40:1, 210:1 and 1680:1. At this juncture, it is useful to briefly recount the exposure conditions in the earlier study of TDE conducted by Mauderly et al. (1987) in which F344 rats exposed to a high concentration of diesel exhaust for up to 30 months had an increased prevalence of lung tumors. The exhaust for that study was from a 1980 Model 5.7 L General Motors Engine operated on a dynamometer with a variable load repeating the U.S. Federal Test Procedure urban certification cycle. The fuel contained 30% aromatics and 0.3% sulfur. The exhaust particles had a mass median aerodynamic diameter of about 0.25 micrometers and about 12% was solvent extractable organic compounds. The exhaust for the lowest dilution level (highest concentration of exhaust constituents) was diluted 10:1. At the lowest dilution and, thus, the highest exposure level, the exposure atmosphere contained: particulate mass, 7,080 µg/m 3 ; carbon monoxide, 30 ppm; Nitric 26

29 Oxide, 10 ppm; Nitrogen Dioxide, 0.7 ppm; hydrocarbon vapor, 13 ppm; and carbon dioxide, 0.7%. As noted earlier, the lowest dilution ratio, and, thus, the highest exhaust constituent concentration for the ACES Phase 3B studies, was selected to achieve the highest level that could be used without having excessive adverse effects solely from the level exposure to NO 2, a prominent constituent in the whole diesel exhaust. The HEI report by Mauderly and McDonald (2012) contains detailed results on the characterization of the exposure chamber atmosphere in ACES (see Tables 22, 23 and 24 of that report). Suffice it to note here that the targeted concentrations of NO 2 were achieved and the expected concentrations of other key constituents were observed. Specifically, for the high, medium and low exposure levels the results were as follows: chamber PM (by gravimetric measurement) 9.7, 1.7 and 0.8 µg/m 3 ; NO 2.9, 0.5, and 0.41 ppm; NO 2 4.0, 0.07 and 0.11 ppm; and NO x 6.9, 1.2 and 0.15 ppm. At the lowest dilution and, thus, highest exposure level, the other key emission constituents present included: Carbon Monoxide, 3.1 ppm; CO 2, 2886 ppm; and Total Hydrocarbons, 0.1 ppm. One to two regeneration events occurred during each 16-hour cycle indicating the engine was operating as would be expected if it were on an on-road tractor. As part of the Phase 3B effort, a large scale study was conducted with strain C57BL/6 mice with exposures of either 1 or 3 months. Each exposure group and the control group includes 132 mice with equal numbers of each gender. The three month exposures of the mice were carried out in February to June The observations included hematology, serum chemistry, bronchioalveolar lavage, complete necropsies, lung epithelial cell proliferation and detailed histopathology. These observations will provide a complete characterization of any potential exposure-related biological effects. Results of that study will be reported in McDonald et al. (2012). The core of the ACES Phase 3B effort is a large scale study conducted with Wistar rats (strain HsdRecHan:Wist) to test the ACES core hypothesis concerning potential carcinogen effects of exposure to NTDE. As explained in the description of the ACES Phase 3B effort, this strain of rat was purposefully selected as an alternative to the F344 rats used in the earlier Lovelace studies (McDonald et al. 2012). The rat exposures were started in May Each of the 3 exposure level groups and control group includes 280 rats (equal number of each gender). Twenty rats are to be used at 1, 3, 12 and 24 months of exposure for observations such as those 27

30 described for mice. In addition, pulmonary function evaluations are being performed. Results of observations in the rat study through 12 months of exposure will be reported in McDonald et al. (2012). Most importantly, 200 rats from each group will be available for long-term observations of lung tumors and other disease endpoints with exposures continuing for at least 24 months. A decision will be made no later than at 23 months of exposure as to the merits of continuing the exposures for 30 months. This would be similar to the approach used by Mauderly et al. (1987) in studying TDE. In addition to the core studies in mice and rats at LRRI, with extensive observations by LRRI scientists, the HEI has provided funding to four other research teams to conduct complementary evaluations of specimens provided by LRRI to each team. These studies include evaluating blood from exposed animals for micronucleus formation (Jeffrey Bennis, Litton Laboratories, Rochester, NY), examining tissues for evidence of vascular inflammation and fibrosis (Daniel Conklin, University of Louisville, Louisville, KY), evaluation of genotoxicity (Lance Hallbert, University of Texas-Galveston, Galveston, TX) and evaluation of cardiovascular function (Qinghua Sun, The Ohio State University, Columbus, OH). It is our understanding that a report (McDonald et al. 2012) on the results of the ACES animal studies with exposures of up to 12 months duration is being prepared by the investigators under the direction of HEI, will be peer-reviewed by a special HEI Review Committee and will be submitted to IARC prior to the June 2012 meeting. In anticipating preliminary results of the ACES Phase 3B rat study, it is important to recall that Mauderly et al. (1989, 1990) found modest respiratory tract pathology in rats chronically exposed to 9.5 ppm NO 2 for 7 hours/day. This equates to 66.5 ppm-hour NO 2 exposure/day, and as noted earlier, was viewed as a Maximum Tolerated Dose (MTD) for a long-term study cancer bioassay, such as ACES. The highest exposure concentration in the ACES study is 4.0 ppm NO 2 which with 16-hours of exposure per day equates to 64 ppm-hours of exposure/day, only slightly lower than the 66.5 ppm-hours/day studied by Mauderly et al. (1989, 1990). In using the daily exposure metric (concentration-time) to set the MTD, it was assumed that the factor of about two difference in exposure rate, expressed as ppm concentration, would not have a major influence on the effectiveness of the NO 2 producing effects. Thus, it is reasonable to expect that the rats at the highest exposure level in the ACES study will have NO 2-28

31 induced respiratory tract effects similar to those observed by Mauderly et al. (1989, 1990) in their study of NO 2 alone. 9. Quantitative and Qualitative Differences in NTDE Compared to TDE In the following sections, qualitative and quantitative differences between NTDE and TDE are reviewed. For each parameter, the situation with regard to TDE is described as it existed at the time of the earlier IARC (1989) review giving special attention to particular parameters mentioned in the Monogoraph. Some parameters reviewed below were not discussed in the IARC Monograph, but have been raised by others after the 1988 review as being important to the potential association of TDE with health effects. The discussion of TDE is then followed by presentation of detailed findings on NTDE. Traditional Diesel Exhaust Particulate Matter In the earlier Monograph (IARC, 1989), TDE was characterized as having a significantly higher concentration of particulate matter than that from gasoline-fueled vehicles, and that, in general, heavy-duty diesel trucks emitted up to 40 times more particulate than catalyst-equipped gasoline-fueled vehicles. IARC estimated that the composition of the particles was approximately 80 percent elemental carbon. In a later analysis, the California Air Resources Board (CARB, 1998a,b,c) estimated that some light-duty diesel engines could emit 50 to 80 times, and some heavy-duty diesel engines 100 to 200 times more particulate mass than typical 3-way catalyst-equipped gasoline engines. CARB similarly estimated that the amount of elemental carbon (EC), in the average diesel particle, typically ranged up to 71 percent. CARB indicated that TDE particles were comprised (by weight) of carbon (88.3 percent), oxygen (4.9 percent), hydrogen (2.6 percent), sulfur (2.5 percent), metals (1.2 percent), and nitrogen (0.5 percent). The fundamental premise was that the particles contained in TDE were mainly aggregates of spherical elemental carbon particles coated with organic and inorganic substances. It was also assumed that the inorganic fraction consisted of small solid carbon particles, ranging from 0.01 to 0.08 micrometers in size, along with sulfur, oxygen, hydro carbons, sulfate (SO 4 ), CO and NOx. The Diesel Health Assessment Document (HAD), prepared by the U.S. EPA (2002), reached conclusions similar to those of IARC and CARB regarding the characteristics and composition of TDE. More specifically, the document noted that TDE particles are primary spherical particles consisting of solid carbonaceous (EC) material and ash (trace metals and other 29

32 elements), absorbed onto which are added organic and sulfur compounds (sulfate) combined with other condensed material (Fig. 1). EPA concluded that the diesel exhaust particles were typically composed of 75% EC (ranging up to 90%), 20% OC (ranging down to 7%), and small amounts of sulfate, nitrate, trace elements, water, and unidentified compounds. The earlier Monograph (IARC, 1989) included a table that summarized emission data on various diesel and gasoline engines ( era) operated on the Federal Test Procedure cycle. The total particulate phase emissions for a heavy-duty diesel vehicle, a light-duty diesel vehicle, a gasoline vehicle without catalytic converter and a gasoline vehicle with catalytic converter were 1036, 246, 62 and 11 mg/km, respectively. The diesel engines of that era operating on high sulfur content fuel can be viewed as producing TDE. The gasoline vehicle operated without a catalytic converter can be viewed as producing TGE and the gasoline vehicle operated with a catalytic converter can be viewed as producing modern gasoline engine exhaust. However, it should be emphasized that the engine and fuel gasoline technology continued to evolve post-1980s (Colucci, 2004). In the sections that follow on the characterization of NTDE, comparisons are made to TDE when data are available. In addition, to provide added perspective some comparisons are made to emissions from modern gasoline and compressed natural gas (CNG) vehicles. The comparisons to gasoline-fueled vehicles are relevant to the forthcoming IARC review which will evaluate both gasoline engine exhaust and diesel engine exhaust as to their human carcinogenic hazard classification. NTDE Emissions are Lower than TDE The results of the detailed characterization study of four engines (compliant with the 2007-EPA emissions Standard) by Khalek et al. (2011) show that the PM emissions as well as the other three regulated emissions (CO, NMHC, and NO x ) were well below the applicable 2007 standards and remarkably lower than the 1998 standard (Table 7) (Khalek et al. 2011). Indeed, the PM emissions were an 86% reduction relative to the 2007 standard and a 99% reduction relative to the 1998 standard (Recall Figure 2). It is clear that the PM emission levels from new technology heavy-duty diesel engines have been reduced to near-zero levels not unlike those from modern gasoline-fueled, 3-way catalyst equipped (MGE) passenger cars. Indeed, in most cases, the PM emission rates for NTDE are well below 0.01 g/mi. (which is equivalent to the PM emission rate for low-emission gasoline-fueled passenger cars) and are similar to the proposed 30

33 California Air Resources Board Low Emission Vehicle (LEV) III PM standard of.003 g/mi for 2017 and later model year passenger cars. (Herner, et al. 2009; Khalek et al. 2011) (Fig. 5). As reviewed in Hesterberg et al. (2011), multiple recent studies of the emissions (g/mile) from heavy-duty transit buses operated with Diesel Particulate Filters have shown that NTDE particulate mass emissions are not significantly higher than other technologies, but instead are similar to the PM emission levels from low-emission CNG-fueled (Ayala et al. 2002; Ayala et al. 2003; Gautam et al. 2005; Lanni et al. 2003); LeTavec et al. 2002; McCormick et al. 1999; Northeast et al, 2000; Norton et al, 1999; Wang et al. 1997) (Fig. 6). While TDE transit bus PM emissions were 0.75 g/mile, the levels for NTDE, are less than 5% of that for TDE. This result holds whether testing is done on the Central Business District cycle, or on other emission test cycles. A similar result also applies if NTDE PM emission levels are compared to gasolinefueled vehicles as reviewed in Hesterberg et al. (2011). To make a comparison with gasoline fueled vehicles, data from passenger cars are used since current transit buses are not fueled with gasoline. As shown in Figures 7 and 8), particulate mass emissions (g/mile) for NTDE are quite similar to modern gasoline (and CNG-fueled) vehicles. (Ahlvik, 2002; Rijkeboer et al, 1994). The passenger car with TDE PM emissions was found to emit 0.13 g/mile, while the levels are substantially lower for NTDE, CNG and modern gasoline vehicles (0.0019, , and g/mile, respectively). From a statistical standpoint, the NTDE, CNG, and modern gasoline passenger vehicles are significantly different from the TDE vehicles, while the NTDE passenger cars are not significantly different from the modern gasoline or CNG vehicles (Fig. 9). In summary, data developed since 1989 clearly show that the particulate mass emissions rates from NTDE are substantially lower than those for TDE, and are statistically indistinguishable from the near-zero PM emission levels seen from modern low-emission gasoline-fueled 3-way catalyst equipped vehicles and CNG-fueled vehicles. Thus, the primary emission constituent of concern (PM) -- the emission constituent that served as the focus of IARC s evaluation of diesel engine exhaust -- has been virtually eliminated and reduced in NTDE to the near zero levels of modern gasoline-fueled vehicles equipped with 3-way catalysts. NTDE Particulate Matter has Different Composition than TDE Recall that the particulate matter in TDE was primarily elemental carbon (frequently on the order of 80%). In contrast, the near-zero amount of PM emitted from new-technology diesel 31

34 engines evaluated in the ACES program contain only 13% elemental carbon (Khalek et al. 2011). Thus, the soot or carbon core fraction of NTDE is largely nonexistent. Other studies have shown that elemental carbon represents a small portion of the total carbon (TC) fraction of NTDE. For NTDE, elemental carbon (EC) represented only 17% of the total carbon (TC) (TC = EC + organic carbon (OC). For particulate emissions from CNG-fueled and port fuel-injection gasoline engines, elemental carbon represented 3% and 5%, respectively, of the total carbon (Holmén and Ayala, 2002; Lev-On et al., 2002; Schauer et al., 2008; Liu et al. 2009a). Further, the portion of TC present as EC for NTDE and CNG are not significantly affected by engine test cycle or workload. In contrast, the portion of TC present as EC for TDE increases markedly (from approximately 60% to 90%) as the workload increases from the steady-state cycle to the transient Central Business District cycle. In contrast with the PM contained in TDE that served as the basis for the earlier 1989 IARC evaluation, the near-zero levels of PM found in NTDE are dominated by sulfate (53%) and organic carbon (30%) -- not a solid carbon core (Fig. 10). The EC has been largely eliminated (Biswas, et al. 2009; Kittelson et al. 2009). To provide added perspective, Figure 10 also shows composition data for a modern gasoline-fueled vehicle equipped with a 3-way catalytic converter in the exhaust line (Ahlvik, 2002). Kittelson et al. (2006) conducted a study in which they varied the sulfur content of the diesel fuel from 2 up to 44 ppm. They found that the nitrate, volatile organics and carbon fractions were relatively constant for all the sulfur levels while the sulfate fraction increased monotonically with increasing fuel sulfur concentration (Fig. 11). It is noteworthy that the elemental carbon fraction was extraordinarily low when the sulfur content of the fuel was 2 or 9 ppm. Grose et al. (2006) has shown that the nanoparticle emissions contained in NTDE are predominantly ammonium sulfates and sulfuric acid, which are fully water-soluble. Soluble sulfate particles, which will tend to undergo dissolution in the lungs, are of low toxicity. (Grahame and Schlesinger, 2005; Reiss, et al. 2007; Schlesinger, et al. 2003, 2007). In addition, due to artifact formation during sampling procedures, and further considering real-world dilution ratios, the actual concentrations of organic carbon emissions from newtechnology diesel engines are likely to be just 10% of what is measured through laboratory sampling techniques (Robinson, et al. 2007). 32

35 In sum, compared against TDE, NTDE represents a 99.7% reduction in EC, a more than 93% reduction in OC, and a greater than 90% reduction in PAHs. (Liu, et al. 2008a). The bulk of any remaining nucleation mode particles in NTDE is sulfate, and, to a lesser extent, volatile organics, which disappear through evaporation. (Biswas, et al. 2008). Accordingly, another assumption relating to TDE -- that diesel PM is dominated by high levels of organic carbon compounds and a solid carbon core -- is fundamentally inapplicable as it pertains to NTDE. Another key premise in the earlier review (IARC, 1989) relating to evaluating the health effects potentially attributable to TDE is that it contains many PAHS and at least 10 times more nitroarenes than gasoline engines. The Monograph identified 60 agents in engine exhaust (not specified as to being found in diesel or gasoline engine exhaust or both) that had been evaluated by IARC. The CARB (1998a,b,c) identified over 40 components of TDE had been listed as toxic air contaminants (TAC) or hazardous air pollutants (HAP) by U.S. EPA and other agencies. The speciated emission components of NTDE are, again, fundamentally different from what was assumed to be present in TDE. Khalek et al. (2011) found that the 40 TACs previously thought to be in TDE were reduced in NTDE by up to 99% or are present in zero-equivalent amounts (including amounts at or below the detection limit), or both (Table 8). These results -- like all of the other results reported from the ACES Phase 1 program -- are very significant since they were obtained with engines operating on an exceedingly rigorous 16-hour test cycle (including urban, creep, transient and cruise mode conditions). The cycle was specifically designed to generate higher-end emission levels (Clark et al. 2007) rather than from engines operated over the 20-minute FTP transient engine-certification test cycle. Similarly, a comparison of a 2004 model year engine and a 2007 model year engine equipped with a catalyzed DPF after-treatment system and a crankcase ventilation coalescer has shown that NTDE contains dramatically reduced levels of many of the compounds that could be identified and quantified in the 2004 model year engine. That included compounds such as formaldehyde and acetaldehyde for which concentrations were dramatically reduced (Liu et al., 2009b). Many of the compounds were below the limits of detection (Table 9). The catalyzed after-treatment system and crank case ventilation coalescer are typical of those used in commercial 2007 on-road heavy-duty units. As shown in Figures 12, 13 and 14, when the emissions of the 2007 engine with contemporary emission controls was compared to the 33

36 emissions from the 2004 engine there was a marked reduction in polycyclic aromatic hydrocarbons (PAHs), nitro-pahs, and oxygenated-pahs (Liu et al. 2010). Thus, NTDE simply does not contain the levels of specific elements that prompted regulatory analyses and concerns at the time of IARC s evaluation of TDE in Semi-volatile Organic Fraction of NTDE is Different than TDE The earlier Monograph (IARC, 1989) also assumed that the sponge-like structure and large surface area of TDE particles made them an excellent carrier for organic compounds of low volatility, and that those compounds resided on the particulate surface (as a liquid) or were included inside the particle, or both. Other assumptions were that the majority of the soluble organic fraction (SOF) was adsorbed onto the surface of the EC core, that the SOF accounted for up to 45% of the total particulate mass, and that the sulfate fraction of diesel exhaust PM could contribute up to 14 percent of the diesel exhaust particle. The ACES Phase 1 study (Khalek et al. 2011) has demonstrated that the semi-volatile phase compounds contained in NTDE have been reduced to extremely low levels, accounting for only 1.4% of the organic carbon fraction (Fig. 15). Of that negligible amount, alkanes (45%) and polar compounds (31%) dominate. PAHs, hopanes and steranes are present in near-zero amounts, ranging from just 6%-9% of the already-miniscule semi-volative phase. NitroPAHs and oxypahs are present in even closer-to-zero amounts, a mere 1% of the semi-volatile phase. Significantly, when compared to TDE, NTDE has 99% reductions in a wide variety of PAH compounds, including both semi-volatile low molecular weight three- to four-ring PAHs, as well as medium to higher molecular weight PAHs, which are generally below the detection limit (Liu, et al., 2008a; Pakbin, et al., 2009). NTDE also has 96%-98% reductions compared to TDE in other particulate organic species, including n- alkanes, hopanes, and steranes, when compared to TDE. (Pakbin, et al ) Similar reductions of C1, C2, and C10 through C33 particle-phase and semi-volatile organic compound species in NTDE were noted by Liu, et al. (2010) (Table 9). All of these data confirm that the original consideration regarding the semi-volatile fraction of TDE does not hold for NTDE. NTDE Contains Lower Amounts of Unregulated Pollutants than TDE The earlier Monograph (IARC, 1989) assumed that TDE might contain a significant amount of several unregulated pollutants of concern. The ACES Phase 1 study measurements for 34

37 a number of classes of compounds of interest are shown in Table 10) (Khalek et al. 2011). Even using conservative estimates from the various measurement techniques used in the ACES program, NTDE has substantial reductions (71% to 99%) in the emissions of unregulated pollutants when compared against 2004-technology engines. Moreover, particle-bound trace metals and elements also have been reduced very significantly (by an average of 98%) in NTDE (Khalek et al. 2011). It is important to recall that earlier TDE engines (typical of ) likely had much higher emissions than the circa 2000 engines with improved TDE profiles. As detailed in the table set forth below (Table 11 (Khalek et al. 2011), NTDE contains substantially less PAHs than found in emissions from earlier model year engine technologies. As noted, PAHs with more than four rings (except fluoranthene and pyrene) have been reduced below the detection limit, and nitropah compounds have been reduced by 99%. Thus, the exhaust emission compounds of potential concern for producing health effects have been reduced to near-zero levels in NTDE. It is also apparent that the NTDE aftertreatment systems are not catalyzing the formation of other potential contaminants based on the extensive chemical characterization of NTDE performed to date. If unique chemical species are present in NTDE, they are at extraordinarily low concentrations that would not pose a health hazard. The net result is that the amounts of both regulated and unregulated compounds contained in NTDE are very similar to those found in the emissions from advanced-technology compressed natural gas engines equipped with catalyzed mufflers. (Hesterberg, et al. 2008). On the other hand, when compared against NTDE, CNG-fueled engines have been found to produce an order of magnitude more carbonyls (especially formaldehyde), and two orders of magnitude more ethylene and propylene emissions. (Lanni, et al ) In particular, when compared against the exhaust from CNG-fueled engines, NTDE has significantly lower emissions of 1, 3-butadiene (i.e., non-detect levels), benzene, toluene, and carbonyls (especially formaldehyde); similarly low emissions of PAHs; and significantly lower specific mutagenic activity, and mutagen emissions. (Kado, et al ) In summary, it is our opinion that NTDE does not contain significant amounts of any unregulated or regulated pollutants that might be of concern from a public health perspective. NTDE Particulate Mass is Fundamentally Different than TDE Particulate Mass A core assumption regarding TDE in the earlier evaluation (IARC, 1989) was that diesel exhaust contains a number of toxicologically relevant compounds such as benzene, toluene, 35

38 xylene and PAHs, and that these PAH compounds were primarily absorbed onto particles. Significantly, much of the information regarding the genotoxicity of TDE was obtained using diesel exhaust particles or organic solvent extracts of diesel exhaust particles. As detailed above, the nature and composition of diesel exhaust particles in NTDE have changed dramatically and fundamentally from the TDE (emitted from 1970s and 1980s-era diesel engines) that IARC (1989) evaluated earlier by IARC (1989). The EC core has been virtually eliminated from NTDE. Instead, the very low concentration nanoparticle emissions in NTDE have a sulfate-rich composition primarily associated with the nucleation of sulfates downstream from the after-treatment systems. This type of sulfate-rich composition differs from the hydrocarbon-rich composition associated with the nuclei mode particles in TDE. (Tobias, et al ) The relative absence of insoluble elemental carbon, and the presence instead of a larger portion of sulfates, should result in the nanoparticles in NTDE being relatively biosoluble compared to the EC rich particles in TDE. Given this biosolubility and the very low concentrations of NTDE particle mass, it is very unlikely that NTDE could result in any respiratory tract accumulation of particle mass. Furthermore, especially when considered in light of the near-zero concentrations of the organic compounds found in NTDE (if found at all), the earlier in vitro findings relating to TDE particles and their extracts are not germane to NTDE. Lower Fine Particle Emissions from NTDE Concern was expressed as early as the 1980s that more fine particles could be formed as a result of then-emerging new diesel engine technologies, which could pose a potential health hazard. It is now known that this hypothesized hazard does not exist. Kittleson et al. (2006), using a novel on-road experimental setup demonstrated the impact of exhaust after-treatment systems in reducing fine particles emissions from diesel engines. The ACES Phase 1 study revealed that the average total number of particles in NTDE (from engines operating on the FTP transient cycle) was 99% lower than from a 2004 technology engine (and 89% lower when operating on a cycle that triggers regeneration events) (Fig. 16) (Khalek et al. 2011). Thus, the number of particles contained in NTDE has been dramatically reduced -- even more so when compared with TDE (as opposed to a 2004 model year engine) and, thus, should not raise any unique health concerns. In fact, the particle number concentration emissions contained in NTDE are well below typical urban ambient air concentrations, and amount to a 10,000-fold reduction when compared 36

39 against older diesel engines not equipped with DPFs. (Barone, et al., 2010.) Other studies have confirmed that the particle numbers contained in NTDE have been lowered to below ambient background levels. (Kittelson, et al ) In fact, particle number emissions from NTDE on average, about two orders of magnitude lower than TDE. (Holmén, et al. 2002, 2004). Further, under higher load conditions, the particle count from NTDE is essentially undetectable when compared against ambient background particle counts. Still other studies have confirmed that the particle number emissions contained in NTDE are more than three orders of magnitude lower than TDE, and at least one order of magnitude lower than a gasoline vehicle. (Bosteels, et al ) In another recent study analyzing the impact of fuel sulfur content on PM emissions, lower nuclei-mode particulate emissions were observed when ULSD fuel (<15 ppm) was used in place of low-sulfur (308 ppm) diesel fuel (Liu, et al., 2007) (Fig. 17). It is apparent that the significant reduction of sulfur content in diesel fuel resulting from the adoption of the ULSD fuel standards (<15 ppm) has played a role in reducing fine particle emissions as well as allowing the use of catalytic exhaust after-treatment systems. Indeed, there are reports from Denmark (Wahlin et al. 2001) and England (Jones et al. 2012) that introduction of very low sulfur content diesel fuel in those countries resulted in substantial reductions in ambient air particle number concentrations. Herner et al. (2011) have investigated the role of both sulfur storage and exhaust temperature as determinants of the occurrence of nucleation mode particles. Their findings were reviewed by Hesterberg et al. (2011, 2012b) who also noted the extent to which the sulfate particles should not be of concern from either due to direct toxicity or from the standpoint of accumulating in the respiratory tract. In summary, contrary to the concern that new diesel technologies (including DPFs) could augment the formation of particles, advanced DPFs operating on ULSD are highly efficient in suppressing, if not completely eliminating, the PM nucleation mode, and exhibit up to a fold reduction (or even more) in nucleation mode particles when compared with TDE. (Biswas et al. 2008). Consequently, in this very important aspect, NTDE, resulting from the combustion of ULSD, is again fundamentally different from what was assumed to be the case for TDE. This provides additional support for the conclusion that any evaluation of TDE should not automatically apply to NTDE. 37

40 10. Experimental Studies Evaluating Potential Health Effects of NTDE Many reports on the health effects of diesel exhaust have been published in recent years (Hesterberg et al. 2012b). A detailed review of those reports indicates that essentially all of those reports involve the study of TDE. It is not surprising that few studies have been conducted with engines producing NTDE since they have only recently become available. Another factor discouraging any studies on NTDE is the extremely clean nature of the NTDE. Even a cursory review by a biomedical investigator of the literature on NTDE characteristics would suggest that NTDE has a very low likelihood of producing any adverse effects in the typical toxicity assays. To be candid, there are limited incentives for scientists to undertake studies that are not likely to demonstrate adverse effects. This emphasizes the importance of the ACES Program that was created specifically to evaluate potential health effects of protracted, low dilution (high concentration) NTDE exposures, including carcinogenic responses. As noted, the initial ACES Phase 3B effort included studies on mice exposed for up to 3 months and rats exposed for at least 24 months and, most likely for 30 months. The McDonald et al. (2012) HEI report describes findings in the mouse studies and for rats exposed for 12 months. That report should be available prior to the IARC June 2012 meeting. Table 12 was compiled to help place the concentrations of key constituents in the recently initiated ACES chronic inhalation exposure studies (McDonald et al., 2012) in perspective relative to previous studies with TDE (Mauderly et al. 1987), Carbon Black (Nikula et al. 1995) and NO 2 alone (Mauderly et al. 1989, 1990). All of these chronic inhalation exposure studies were conducted at the LRRI in Albuquerque, NM in the same basic facilities being used for the ACES study. The Mauderly et al. (1987) study with TDE was one of the earliest studies demonstrating that chronic exposure of rats to low dilutions of whole diesel exhaust, with high concentrations of particles, resulted in an increased prevalence of lung tumors. The Mauderly et al. (1987) study was unique in several ways. First, the Mauderly et al. (1987) study involved 30 months of exposure and observation to maximize the potential for detecting an excess of tumors. This is very different than typical cancer bioassays, including those conducted for the NTP, which typically are only 24 months in duration. Second, beyond evaluating the potential carcinogenic effects of TDE, parallel studies were conducted to evaluate many other endpoints (McClellan et al. 1982, 1986). This included concurrent research on the deposition and retention of the diesel soot in the lungs (Wolff et al. 1987, 1989). This research 38

41 demonstrated impairment of clearance and an accumulation of soot in the lungs of the rats at the highest exposure concentrations, accumulation substantially in excess of that predicted from the kinetics at lower exposure concentrations. That finding, as well as other evidence as reviewed in Mauderly and McCunney (1996b); Mauderly (1997); Hesterberg et al. (2005) Wolff et al. (1987, 1989), suggested that the increased prevalence of lung tumors observed in rats with protracted exposure to high concentrations of TDE was likely a result of an overload phenomena associated with the elemental carbon core of the particles and independent of any effect of hydrocarbon compounds such as the PAHs. To further test the particle overload hypothesis, the Nikula et al. (1995) study was conducted with rats exposed to carbon black, essentially pure elemental carbon devoid of hydrocarbons. As predicted, an increased prevalence of lung tumors was observed. Similar results were found by Heinrich et al. (1995) in studies with carbon black exposures at high concentrations using Wistar rats. It may be noted (Table 12) that the exposure intensity (in µg/m 3.hr/week) in the Nikula et al. (1995) study at the two exposure concentrations studied bracketed that of the Mauderly et al. (1987) study with TDE. An additional study (Mauderly et al. 1989, 1990) involved exposure to NO 2 alone, a major oxidant gaseous constituent in both TDE and NTDE. The exposure concentration studied, 9.5 ppm, was substantially higher than was present in the TDE exposure of Mauderly et al. (1987). As discussed earlier, histopathologic changes were observed in the lungs of the rats exposed only to a high concentration of NO 2. As discussed earlier, the NO 2 exposure intensity of 66.5 ppm.hrs/day was considered by the HEI Oversight Committee to be a Maximum Tolerated Dose, based on effects in the respiratory tract, and used as a basis for the lowest dilution used in the ACES animal study. In the ACES rat study now in progress, at the lowest dilutions and, thus, the highest concentration of exhaust constituents (i.e. the Maximum Tolerated Dose based on NO 2 ), it is to be expected that respiratory tract effects will be observed from the nares to the conducting airway as expected for exposure to high concentrations of an oxidant gas such as NO 2. The effects should be quite similar to those previously reported by Mauderly et al. (1989, 1990) for 12 or 24 months of exposure to NO 2 alone. It is important to recall that the NO 2 study of Mauderly et al. (1989, 1990) continued through 24 months of exposure, the duration of most cancer bioassays. They did not observe an excess of lung tumors related to the protracted high 39

42 concentration NO 2 exposure. The findings reported on the NTDE exposures for up to 12 months in the McDonald et al. (2012) report should be carefully reviewed by the IARC Working Group. However, it will be important to recognize that the ACES rat bioassay results of greatest interest will be the prevalence of lung tumors in rats exposed to diluted whole exhaust compared to sham-exposed controls, data that will not become available until late 2012 (Mauderly, 2010). It is our view that the ACES results to date, and the prospects for additional data when the ACES Phase 3B effort is concluded, offers strong support for IARC evaluating NTDE in June 2012 and placing it in Group 3, not classifiable as to its carcinogenicity to humans. 11. Summary The information reviewed above comparing NTDE to TDE has shown that in the case of technology specific emissions (such as diesel exhaust), technological advances can have a profound impact on reducing and changing the composition of emissions. This situation is in sharp contrast to that for a particular chemical agent that has physical properties, including those that determine its hazard potential, which never change. Major revolutionary advances have been made in diesel technology, especially during the last decade, which have impacted on exhaust emissions. Those advances which are integrated as a system include: (a) engine improvements including the use of exhaust gas recirculation; (b) use of ultra-low sulfur diesel fuel; (c) exhaust after-treatment including oxidative catalysts and wallflow particulate matter traps; and (d) electronic sensing and computerized control systems. The new systems are extraordinarily effective in reducing and changing particulate matter exhaust as compared to TDE emissions. The key changes are: lower particulate mass emissions, different chemical composition, lower fine particle number emissions, altered composition of the semivolatile fraction, and lower concentrations of unregulated pollutants. Thus, the NTDE emissions are substantially different than TDE emissions. Moreover, the NTDE emissions are now similar to or lower than those of modern CNG or modern gasoline-fueled engines. The extensive characterization of NTDE has clearly established that the emissions are substantially lower than the applicable, very stringent regulatory emission standards. Moreover, the detailed chemical characterization gives confidence that the emissions do not contain any unique constituents that might pose a hazard to human health. The new technology heavy-duty engines with ultra-low particulate emissions were introduced into the market for on-road use in 2007 as required by U.S. regulations, and have been well received by customers. Starting in 40

43 2010, the engines marketed in the USA continue to have ultra-low particulate mass emissions and, in addition, even lower NO x emissions than the 2007 model engines. In future years, the number of NTDE units will increase and the number of TDE units will decrease in the on-road fleet. Moreover, a similar shift will follow with off-road diesel-power equipment. To further validate the lack of health hazard of NTDE, exhaustive investigations are now underway in which mice and rats are being exposed to graded concentrations of whole NTDE. The highest concentrations being studied are a dilution of only 40:1 of engine-out emissions, a dilution selected to limit potential effects of the NO 2. However, the high concentration NO 2 component at the highest exposure level is expected to produce modest histopathological changes in the respiratory tract. The bioassay with rats exposed for 30 months (16 hr/day, 5 days/week) is similar in design to the earlier studies with TDE in which an excess of lung tumors was observed at the highest particulate mass concentrations (the lowest dilutions of whole TDE). Thus, the results of the NTDE and TDE bioassays can be directly compared when the NTDE bioassay is completed and reported in Moreover, it is clear that the results of the NTDE bioassay will provide a direct evaluation of the ACES core (null) hypothesis that the NTDE exposure will not cause an increase in tumor formation or substantial toxic health effects in rats and mice at the highest concentration of exhaust that can be used compared to animals exposed to clean air, although some biological effects may occur. Based on the remarkable differences in concentration and composition of NTDE compared to TDE, it is our recommendation that NTDE should be evaluated and classified separately from TDE by the IARC Working Group in June Conclusions The use of diesel engines as reliable and efficient sources of power to move goods and people and meet other critical needs of society has steadily grown over the past century. During the past half century, concerns arose over the impact of diesel engine exhaust on visibility and human health and more recently on climate change. Those concerns were soon reflected in increasingly more stringent regulations to limit engine emissions. The need for progressively lower emission standards was reinforced by increasingly stringent National Ambient Air Quality Standards for Particulate Matter, Ozone and Nitrogen Dioxides. In response to the stringent regulations, the manufacturers of diesel engines and refiners of diesel fuel made evolutionary and, more recently, revolutionary advances in diesel technology 41

44 including improved engines, exhaust after-treatment and use of improved, ultra-low sulfur fuels. This new technology is being rapidly introduced into the market to replace traditional diesel engines and fuels. The particulate matter concentration in NTDE is remarkably lower than in TDE and the composition of NTDE is distinctly different than that of TDE. The TDE particles illustrated in Figure 1, with their core of elemental carbon and substantial amount of associated hydrocarbons, are not present in NTDE. It is clear that there have been paradigm-shifting advances in the control of diesel exhaust emissions in response to progressively more stringent regulations. The earlier IARC (1989) review classified whole diesel exhaust, which we characterize as TDE, as a probable human carcinogen, Group 2A. The same IARC Working Group classified whole gasoline exhaust, which we characterize as Traditional Gasoline Exhaust, as a possible human carcinogen, Group 2B. IARC in June 2012 will again review the carcinogenic hazard classification of diesel exhaust and gasoline exhaust. Since the previous IARC review, substantial new information has been published on epidemiological observations relating to workers exposed to TDE and on the mechanisms by which protracted exposure to high concentrations of TDE and other poorly soluble particles produces lung tumors in rats. That new information will need to be critically evaluated by the IARC Working Group as it considers appropriate carcinogenic hazard classifications for whole diesel exhaust. It is our view that whatever classification is given, it should be specifically identified as being applicable to TDE. We recommend, in recognition that NTDE is fundamentally different than TDE, that IARC evaluate and classify NTDE separately from TDE. Likewise, it is appropriate for IARC to recognize that sufficient information is now available for gasoline exhaust to separately evaluate TGE and modern gasoline emissions. This is the approach shown schematically in Table 6. This approach would be similar to the approach taken by IARC (2002) in an earlier review and classification of newly developed biosoluble glass wool fibers as not classifiable as to human carcinogenicity, Group 3. It is our recommendation, based on current scientific information, that it would be appropriate to classify NTDE as Group 3, not classifiable as to human carcinogenicity. Classifying NTDE in Group 3 will serve to distinguish the new technology diesel engine and fuel from the old traditional diesel technology. Most importantly, this distinction will encourage the deployment of ultra-clean diesel technology around the world with a resulting profoundly positive impact on public health. 42

45 Acknowledgments The authors extend a note of appreciation to their many colleagues who have made major contributions to the evolutionary and revolutionary developments in diesel technology since the 1970s and the remarkable advances that have been made in understanding the potential health impacts of diesel emissions. Many of those individuals contributed to the development of information cited in this review and, in some cases, offered specific suggestions that improved the quality of the manuscript. In particular, we acknowledge the helpful reviews by Imad A. Khalek, Southwest Research Institute, and Z. G. (Jerry) Liu, Cummins, Inc. Their reviews were especially useful because they and their colleagues have been major contributors to the literature on characterization of New Technology Diesel Exhaust. The authors would also like to specifically note the valuable input of Charles Lapin, an independent consultant, and Christopher Long and Peter Valberg, Gradient, Consultants to Navistar International. Conflict of Interest Statement The authors have had a long association with private sector firms and organizations striving to develop ultra-clean diesel technology. Roger O. McClellan has served on numerous advisory committees to the U.S. EPA and other government and private organizations on air quality issues. He was first alerted to issues concerning the potential health effects of diesel exhaust emissions from traditional diesel technology while serving on an EPA Advisory Committee in the 1970s. In the late 1970s, he was responsible for providing leadership for initiating the Lovelace organization s pioneering studies of diesel exhaust. From that time to the present time, he has served in an advisory role to the Health Effects Institute, the Engine Manufacturers Association and private firms concerned with diesel technology and its potential health impact. In addition, he has served in an Advisory Role to the U.S. Environmental Protection Agency on setting of air quality standards, including service as Chair of the U.S. Environmental Protection Agency Clean Air Scientific Advisory Committee (CASAC) and service on CASAC Panels for the revision of National Ambient Air Quality Standards for all the criteria pollutants. He served as a member of the Working Group that prepared the IARC (1989) Monograph on Diesel and Gasoline Exhaust and Some Nitroarenes. Thomas W. Hesterberg has been employed by Navistar International since 2002 and has responsibility for coordinating that firm s product stewardship program of which a major component is the development of improved diesel technology. John C. Wall has been employed by Cummins, Inc. since 1986 and 43

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58 Figure 1: Scanning electron micrograph of traditional diesel exhaust particulate matter (from Tschoeke and Mollenhauer, 2010). Primary particles with diameters of less than 10 nanometers that rapidly aggregate to a size distribution that is log-normal and with median diameter of approximately nanometers. The elemental carbon particles adsorb and absorb hydrocarbons, sulfates and trace metals.

59 Figure 2: U.S. EPA particulate emission standards for heavy-duty or road diesel trucks (t) or urban buses (ub) in grams per brake-horse power hour (g/bhp-hr) on the left and as % of unregulated engine emission on the right. For purposes of use of metric units, 1 hp = kw.

60 Figure 3: U.S. EPA NOx emission standards for heavy-duty on-road diesel engines in grams per brake horse power hour (g/bhp-hour) on the left and as % of unregulated emissions on the right. For purpose of use of metric units, 1 hp = kw.

61 Figure 4: Schematic rendering of evolutionary development of advanced diesel technology followed by revolutionary advances occurring with introduction of ultra-low sulfur (<15 ppm) fuel and wall flow diesel particulate filters.

62 Figure 5: Particle mass emissions for traditional diesel exhaust (TDE) vehicle and six vehicles with New Technology Diesel Exhaust (NTDE) configured with Diesel Particulate Filters (DPF) and Selective Catalytic Reduction (SCR) systems (Data from Herner et al. 2009). Emissions are expressed as mg/mile on left and as percent of TDE on right. The number at the top of each bar is particle mass emissions in mg/mile.

63 Figure 6: Particulate emissions for transit buses fueled with diesel fuel (NTDE) or compressed natural gas (CNG) and operated with or without an oxidation catalyst (OC). Emissions are expressed in milligram/mile on the left and as % of TDE on the right. The number at the top of each bar is particle mass emissions in mg/mile. (Data from Hesterberg et al. 2008).

64 Figure 7: Particulate emissions (PM) expressed in mg PM/mile on left and % Traditional Diesel Exhaust (TDE) on right for passenger cars with different engine technologies (data from Ahlvik 2002).

65 Figure 8: Particulate Matter (PM) emissions, expressed as mg PM/mile on left and % Traditional Diesel Exhaust (TDE) on right, for Passenger Cars. Data from Ahlvik (2002) and Rijkeboer et al. (1994) as reviewed by Hesterberg et al. (2011).

66 Figure 9: Average PM Emissions Rate and Composition for all twelve repeats of the 16-hour cycles using all four ACES Engines. (Data taken from animal exposure chambers without animals present; PM mass emissions from constant volume sampler system are 50% lower). (Khalek, et al. 2011).

67 Figure 10. Composition of Particulate Matter from Traditional Diesel Exhaust (TDE) (Kittleson, 1998), New Technology Diesel Exhaust (NTDE) (Khalek et al. 2010) and Modern Gasoline Exhaust (GE) (Cheung et al. 2009).

68 mg Carbon Volatile Organics Nitrate Sulfate Fuel Sulfur Level (ppm) Figure 11: Measured Particulate Matter emissions (Carbon, Volatile Organic Compounds, Sulfate and Nitrate) continuously regenerating diesel particulate filter from a heavy duty diesel engine as a function of fuel sulfur content. (Adapted from Kittelson, et al. 2006).

69 Figure 12: Reduced concentrations of polycyclic aromatic hydrocarbons in emissions from 2007 diesel engine with contemporary emission controls compared to emissions from a 2004 engine without contemporary emission controls (data from Liu et al. 2010).

70 Figure 13: Concentration of nitro-polycyclic aromatic hydrocarbon in 2007 model engine with contemporary emission controls compared to 2004 model engines without contemporary emission controls (left), Liu et al. (2010) and 2007 model (ACES engines) compared to 2000 mode engines (right) (Khalek et al. 2010).

71 ug/bhp-hr % 11.4% 2004 Engine 2007 Engine 9-Anthraaldehyde Benzanthrone Anthraquinone Xanthone 9-Fluorenone Acenaphthenequinone Perinaphthanone Figure 14: Concentration of oxygenated polycyclic aromatic hydrocarbons from 2004 model engine without exhaust after-treatment compared to 2007 model with contemporary controls (data from Liu et al. 2010).

72 Figure 15: Average particle phase semi-volatile emission rate and composition for all twelve repeats of the 16-hour cycles using all four ACES engines (Khalek et al. 2011).